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Nature Reviews. Disease Primers Oct 2023Bladder cancer is a global health issue with sex differences in incidence and prognosis. Bladder cancer has distinct molecular subtypes with multiple pathogenic pathways... (Review)
Review
Bladder cancer is a global health issue with sex differences in incidence and prognosis. Bladder cancer has distinct molecular subtypes with multiple pathogenic pathways depending on whether the disease is non-muscle invasive or muscle invasive. The mutational burden is higher in muscle-invasive than in non-muscle-invasive disease. Commonly mutated genes include TERT, FGFR3, TP53, PIK3CA, STAG2 and genes involved in chromatin modification. Subtyping of both forms of bladder cancer is likely to change considerably with the advent of single-cell analysis methods. Early detection signifies a better disease prognosis; thus, minimally invasive diagnostic options are needed to improve patient outcomes. Urine-based tests are available for disease diagnosis and surveillance, and analysis of blood-based cell-free DNA is a promising tool for the detection of minimal residual disease and metastatic relapse. Transurethral resection is the cornerstone treatment for non-muscle-invasive bladder cancer and intravesical therapy can further improve oncological outcomes. For muscle-invasive bladder cancer, radical cystectomy with neoadjuvant chemotherapy is the standard of care with evidence supporting trimodality therapy. Immune-checkpoint inhibitors have demonstrated benefit in non-muscle-invasive, muscle-invasive and metastatic bladder cancer. Effective management requires a multidisciplinary approach that considers patient characteristics and molecular disease characteristics.
Topics: Humans; Female; Male; Treatment Outcome; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms; Urinary Bladder; Prognosis
PubMed: 37884563
DOI: 10.1038/s41572-023-00468-9 -
European Urology Aug 2023Bladder cancer (BC) is common worldwide and poses a significant public health challenge. External risk factors and the wider exposome (totality of exposure from external... (Review)
Review
CONTEXT
Bladder cancer (BC) is common worldwide and poses a significant public health challenge. External risk factors and the wider exposome (totality of exposure from external and internal factors) contribute significantly to the development of BC. Therefore, establishing a clear understanding of these risk factors is the key to prevention.
OBJECTIVE
To perform an up-to-date systematic review of BC's epidemiology and external risk factors.
EVIDENCE ACQUISITION
Two reviewers (I.J. and S.O.) performed a systematic review using PubMed and Embase in January 2022 and updated it in September 2022. The search was restricted to 4 yr since our previous review in 2018.
EVIDENCE SYNTHESIS
Our search identified 5177 articles and a total of 349 full-text manuscripts. GLOBOCAN data from 2020 revealed an incidence of 573 000 new BC cases and 213 000 deaths worldwide in 2020. The 5-yr prevalence worldwide in 2020 was 1 721 000. Tobacco smoking and occupational exposures (aromatic amines and polycyclic aromatic hydrocarbons) are the most substantial risk factors. In addition, correlative evidence exists for several risk factors, including specific dietary factors, imbalanced microbiome, gene-environment risk factor interactions, diesel exhaust emission exposure, and pelvic radiotherapy.
CONCLUSIONS
We present a contemporary overview of the epidemiology of BC and the current evidence for BC risk factors. Smoking and specific occupational exposures are the most established risk factors. There is emerging evidence for specific dietary factors, imbalanced microbiome, gene-external risk factor interactions, diesel exhaust emission exposure, and pelvic radiotherapy. Further high-quality evidence is required to confirm initial findings and further understand cancer prevention.
PATIENT SUMMARY
Bladder cancer is common, and the most substantial risk factors are smoking and workplace exposure to suspected carcinogens. On-going research to identify avoidable risk factors could reduce the number of people who get bladder cancer.
Topics: Humans; Vehicle Emissions; Risk Factors; Urinary Bladder Neoplasms; Smoking; Tobacco Smoking; Occupational Exposure
PubMed: 37198015
DOI: 10.1016/j.eururo.2023.03.029 -
Nature Jul 2023Loss of the Y chromosome (LOY) is observed in multiple cancer types, including 10-40% of bladder cancers, but its clinical and biological significance is unknown. Here,...
Loss of the Y chromosome (LOY) is observed in multiple cancer types, including 10-40% of bladder cancers, but its clinical and biological significance is unknown. Here, using genomic and transcriptomic studies, we report that LOY correlates with poor prognoses in patients with bladder cancer. We performed in-depth studies of naturally occurring LOY mutant bladder cancer cells as well as those with targeted deletion of Y chromosome by CRISPR-Cas9. Y-positive (Y) and Y-negative (Y) tumours grew similarly in vitro, whereas Y tumours were more aggressive than Y tumours in immune-competent hosts in a T cell-dependent manner. High-dimensional flow cytometric analyses demonstrated that Y tumours promote striking dysfunction or exhaustion of CD8 T cells in the tumour microenvironment. These findings were validated using single-nuclei RNA sequencing and spatial proteomic evaluation of human bladder cancers. Of note, compared with Y tumours, Y tumours exhibited an increased response to anti-PD-1 immune checkpoint blockade therapy in both mice and patients with cancer. Together, these results demonstrate that cancer cells with LOY mutations alter T cell function, promoting T cell exhaustion and sensitizing them to PD-1-targeted immunotherapy. This work provides insights into the basic biology of LOY mutation and potential biomarkers for improving cancer immunotherapy.
Topics: Animals; Humans; Mice; CD8-Positive T-Lymphocytes; Chromosome Deletion; Chromosomes, Human, Y; Proteomics; Tumor Microenvironment; Urinary Bladder Neoplasms; Tumor Escape; Gene Expression Profiling; Genomics; Prognosis; CRISPR-Cas Systems; Gene Editing; In Vitro Techniques; Immune Checkpoint Inhibitors; Flow Cytometry; Immunotherapy
PubMed: 37344596
DOI: 10.1038/s41586-023-06234-x -
International Journal of Molecular... Aug 2023Urothelial carcinoma (UC), the sixth most common cancer in Western countries, includes upper tract urothelial carcinoma (UTUC) and bladder carcinoma (BC) as the most... (Review)
Review
Urothelial carcinoma (UC), the sixth most common cancer in Western countries, includes upper tract urothelial carcinoma (UTUC) and bladder carcinoma (BC) as the most common cancers among UCs (90-95%). BC is the most common cancer and can be a highly heterogeneous disease, including both non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) forms with different oncologic outcomes. Approximately 80% of new BC diagnoses are classified as NMIBC after the initial transurethral resection of the bladder tumor (TURBt). In this setting, intravesical instillation of Bacillus Calmette-Guerin (BCG) is the current standard treatment for intermediate- and high-risk patients. Unfortunately, recurrence occurs in 30% to 40% of patients despite adequate BCG treatment. Radical cystectomy (RC) is currently considered the standard treatment for NMIBC that does not respond to BCG. However, RC is a complex surgical procedure with a recognized high perioperative morbidity that is dependent on the patient, disease behaviors, and surgical factors and is associated with a significant impact on quality of life. Therefore, there is an unmet clinical need for alternative bladder-preserving treatments for patients who desire a bladder-sparing approach or are too frail for major surgery. In this review, we aim to present the strategies in BCG-unresponsive NMIBC, focusing on novel molecular therapeutic targets.
Topics: Humans; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; BCG Vaccine; Non-Muscle Invasive Bladder Neoplasms; Quality of Life; Mycobacterium bovis
PubMed: 37628785
DOI: 10.3390/ijms241612596 -
Frontiers in Immunology 2023Disulfidptosis is a recently discovered form of cell death. However, its biological mechanisms in bladder cancer (BCa) are yet to be understood.
BACKGROUND
Disulfidptosis is a recently discovered form of cell death. However, its biological mechanisms in bladder cancer (BCa) are yet to be understood.
METHODS
Disulfidptosis-related clusters were identified by consensus clustering. A disulfidptosis-related gene (DRG) prognostic model was established and verified in various datasets. A series of experiments including qRT-PCR, immunoblotting, IHC, CCK-8, EdU, wound-healing, transwell, dual-luciferase reporter, and ChIP assays were used to study the biological functions.
RESULTS
We identified two DRG clusters, which exhibited distinct clinicopathological features, prognosis, and tumor immune microenvironment (TIME) landscapes. A DRG prognostic model with ten features (DCBLD2, JAM3, CSPG4, SCEL, GOLGA8A, CNTN1, APLP1, PTPRR, POU5F1, CTSE) was established and verified in several external datasets in terms of prognosis and immunotherapy response prediction. BCa patients with high DRG scores may be characterized by declined survival, inflamed TIME, and elevated tumor mutation burden. Besides, the correlation between DRG score and immune checkpoint genes and chemoradiotherapy-related genes indicated the implication of the model in personalized therapy. Furthermore, random survival forest analysis was performed to select the top important features within the model: POU5F1 and CTSE. qRT-PCR, immunoblotting, and immunohistochemistry assays showed the enhanced expression of CTSE in BCa tumor tissues. A series of phenotypic assays revealed the oncogenetic roles of CTSE in BCa cells. Mechanically, POU5F1 can transactivate CTSE, promoting BCa cell proliferation and metastasis.
CONCLUSIONS
Our study highlighted the disulfidptosis in the regulation of tumor progression, sensitivity to therapy, and survival of BCa patients. POU5F1 and CTSE may be potential therapeutic targets for the clinical treatment of BCa.
Topics: Humans; Cell Proliferation; Cell Transformation, Neoplastic; Prognosis; Carcinogenesis; Urinary Bladder Neoplasms; Tumor Microenvironment
PubMed: 37325625
DOI: 10.3389/fimmu.2023.1198878 -
Molecular Biology Reports Sep 2023Urothelial bladder carcinoma (UC) ranks among the top ten most commonly diagnosed cancers worldwide on an annual basis. The standardized classification system for... (Review)
Review
Urothelial bladder carcinoma (UC) ranks among the top ten most commonly diagnosed cancers worldwide on an annual basis. The standardized classification system for urothelial bladder tumors is the Tumor, Node, Metastasis classification, which reflects differences between non-muscle-invasive bladder carcinoma (NMIBC) and muscle-invasive bladder carcinoma (MIBC) and it depends on the extent to which tumor has infiltrated the bladder wall and other tissues and organs. NMIBC and MIBC exhibit great intrinsic heterogeneity regarding different prognoses, survival, progression, and treatment outcomes. In recent years, studies based on mRNA expression profiling revealed the existence of biologically relevant molecular subtypes of UC, which show variant molecular features that can provide more precise stratification of UC patients. Here, we present a complex classification of UC based on mRNA expression studies and molecular subtypes of NMIBC and MIBC in detail with regard to different mRNA expression profiles, mutational signatures, and infiltration by non-tumor cells. The possible impact of molecular subtyping on treatment decisions and patients' outcomes is outlined, too.
Topics: Humans; Urinary Bladder; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Mutation; Neoplasm Invasiveness
PubMed: 37525073
DOI: 10.1007/s11033-023-08689-7 -
Journal For Immunotherapy of Cancer Oct 2023Immune checkpoint inhibitor (ICI) therapy improves the survival of patients with advanced bladder cancer (BLCA); however, its overall effectiveness is limited, and many...
BACKGROUND
Immune checkpoint inhibitor (ICI) therapy improves the survival of patients with advanced bladder cancer (BLCA); however, its overall effectiveness is limited, and many patients still develop immunotherapy resistance. The leucine-rich repeat and fibronectin type-III domain-containing protein (LRFN) family has previously been implicated in regulating brain dysfunction; however, the mechanisms underlying the effect of LRFN2 on the tumor microenvironment (TME) and immunotherapy remain unclear.
METHODS
Here we combined bulk RNA sequencing, single-cell RNA sequencing, ProcartaPlex multiple immunoassays, functional experiments, and TissueFAXS panoramic tissue quantification assays to demonstrate that LRFN2 shapes a non-inflammatory TME in BLCA.
RESULTS
First, comprehensive multiomics analysis identified LRFN2 as a novel immunosuppressive target specific to BLCA. We found that tumor-intrinsic LRFN2 inhibited the recruitment and functional transition of CD8 T cells by reducing the secretion of pro-inflammatory cytokines and chemokines, and this mechanism was verified in vitro and in vivo. LRFN2 restrained antitumor immunity by inhibiting the infiltration, proliferation, and differentiation of CD8 T cells in vitro. Furthermore, a spatial exclusivity relationship was observed between LRFN2 tumor cells and CD8 T cells and cell markers programmed cell death-1 (PD-1) and T cell factor 1 (TCF-1). Preclinically, LRFN2 knockdown significantly enhanced the efficacy of ICI therapy. Clinically, LRFN2 can predict immunotherapy responses in real-world and public immunotherapy cohorts. Our results reveal a new role for LRFN2 in tumor immune evasion by regulating chemokine secretion and inhibiting CD8 T-cell recruitment and functional transition.
CONCLUSIONS
Thus, LRFN2 represents a new target that can be combined with ICIs to provide a potential treatment option for BLCA.
Topics: Humans; Biological Assay; CD8-Positive T-Lymphocytes; Cell Differentiation; Immunotherapy; Membrane Glycoproteins; Nerve Tissue Proteins; Tumor Microenvironment; Urinary Bladder Neoplasms; Drug Resistance, Neoplasm
PubMed: 37802603
DOI: 10.1136/jitc-2023-007230 -
Cell Proliferation Jul 2023Activation of PI3K/AKT signalling by PTEN loss significantly enhances chemoresistance in bladder cancer. This study aims to evaluate PTEN regulation and identify targets...
Activation of PI3K/AKT signalling by PTEN loss significantly enhances chemoresistance in bladder cancer. This study aims to evaluate PTEN regulation and identify targets that could be used to relieve chemoresistance. Expression of YTHDC1, γ-H2AX and PTEN were detected by IHC assay. Cell Counting Kit-8 assay, colony formation assay and tumour xenograft experiment evaluated cisplatin response. Flow cytometry and comet assay estimated cell apoptosis, cell cycle distribution and DNA repair capability. Quantitative real-time polymerase chain reaction, Western blot and RIP assay assessed binding properties between PTEN mRNA and YTHDC1. Silencing YTHDC1 in bladder cancer cells reduced PTEN expression and activated PI3K/AKT signalling by destabilizing PTEN mRNA in an m A-dependent manner. Low YTHDC1 expression indicated poor cisplatin sensitivity in bladder cancer patients. Reducing YTHDC1 expression promoted drug resistance to cisplatin, while over-expressing YTHDC1 promoted cisplatin sensitivity. Reducing YTHDC1 expression activated DNA damage response, which includes quicker cell cycle recovery, apoptosis evasion and an enhanced DNA repair capability, whereas these effects were attenuated when MK2206, a PI3K/AKT inhibitor was applied. We provide novel evidence that PTEN/PI3K/AKT signalling pathway could be regulated by YTHDC1 in an m A-dependent manner and highlight a critical role of YTHDC1 in cisplatin resistance of bladder cancer.
Topics: Humans; Cisplatin; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Drug Resistance, Neoplasm; Apoptosis; RNA, Messenger; Urinary Bladder Neoplasms; Cell Line, Tumor; Cell Proliferation; PTEN Phosphohydrolase; RNA Splicing Factors; Nerve Tissue Proteins
PubMed: 37070134
DOI: 10.1111/cpr.13404 -
European Review For Medical and... Nov 2023Bladder urothelial carcinoma is a rare condition that primarily affects the elderly and is rare in people under 40 years of age. There is no definitive information about...
OBJECTIVE
Bladder urothelial carcinoma is a rare condition that primarily affects the elderly and is rare in people under 40 years of age. There is no definitive information about the prognosis and clinical behavior of bladder cancer in young individuals. In our study, we aimed to investigate the prognosis and clinicopathological features of bladder tumors in patients under 40.
PATIENTS AND METHODS
A retrospective analysis was performed on patients diagnosed with urothelial neoplasia who underwent bladder surgery between January 2008 and December 2020. The patient's medical records in our cancer database were collected. The study included stage, grade, multifocality, smoking habits, recurrence, and survival. The cases were divided into two groups: those under 40 (Group 1) and those over 40 (Group 2). The clinical and pathological features of young and old patients were compared.
RESULTS
17 patients (14 men and 3 women) under 40 were identified. The age ranged between 19 and 40, and the average was 30.6. One infiltrating urothelial carcinoma (pT1), twelve papillary urothelial carcinomas (pTa), two papillary urothelial neoplasias with low malignant potential, and two urothelial papillomas were all identified by pathology. Dysuria was the primary symptom that initially manifested. Recurrence occurred in two of 12 patients with low-grade papillary urothelial carcinoma in the young patient group. In a similar group of patients over 40, recurrence was detected in 7 out of 10 patients. Patients with urothelial carcinoma under the age of 40 have been noted to have single, small tumors, unlike older patients. No tumor progression was detected in young patients. All young patients are still alive and have not experienced any recurrences. In the group of older patients, tumor progression was observed in 11 patients (16.4%).
CONCLUSIONS
Patients under 40 typically have low-grade and low-stage bladder urothelial cancer. Because urothelial tumors in young people frequently have a good prognosis and seldom recur, transurethral excision is the preferred treatment method for bladder tumors.
Topics: Male; Humans; Female; Adolescent; Aged; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Retrospective Studies; Prognosis; Neoplasm Recurrence, Local
PubMed: 37975369
DOI: 10.26355/eurrev_202311_34320 -
Advanced Science (Weinheim,... Sep 2023Although immune checkpoint blockade (ICB) therapies have been approved for bladder cancer (BLCA), only a minority of patients respond to these therapies, and there is an...
Although immune checkpoint blockade (ICB) therapies have been approved for bladder cancer (BLCA), only a minority of patients respond to these therapies, and there is an urgent need to explore combined therapies. Systematic multi-omics analysis identified S100A5 as a novel immunosuppressive target for BLCA. The expression of S100A5 in malignant cells inhibited CD8 T cell recruitment by decreasing pro-inflammatory chemokine secretion. Furthermore, S100A5 attenuated effector T cell killing of cancer cells by inhibiting CD8 T cell proliferation and cytotoxicity. In addition, S100A5 acted as an oncogene, thereby promoting tumor proliferation and invasion. Targeting S100A5 synergized with the efficacy of anti-PD-1 treatment by enhancing infiltration and cytotoxicity of CD8 T cells in vivo. Clinically, there was a spatially exclusive relationship between S100A5 tumor cells and CD8 T cells in tissue microarrays. Moreover, S100A5 negatively correlated with immunotherapy efficacy in our real-world and several public immunotherapy cohorts. In summary, S100A5 shapes a non-inflamed tumor microenvironment in BLCA by inhibiting the secretion of pro-inflammatory chemokines and the recruitment and cytotoxicity of CD8 T cells. Targeting S100A5 converts cold tumors into hot tumors, thus enhancing the efficacy of ICB therapy in BLCA.
Topics: Humans; CD8-Positive T-Lymphocytes; Urinary Bladder; Immunotherapy; Urinary Bladder Neoplasms; Carcinoma; Tumor Microenvironment
PubMed: 37414584
DOI: 10.1002/advs.202300110